An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis.
An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis.
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DOI：
10.1126/sciimmunol.abn0175
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发表时间：
2022-06-03
影响因子：
24.8
通讯作者：
McKenzie ANJ
中科院分区：
文献类型：
--
作者：
Jou E;Rodriguez-Rodriguez N;Ferreira AF;Jolin HE;Clark PA;Sawmynaden K;Ko M;Murphy JE;Mannion J;Ward C;Matthews DJ;Buczacki SJA;McKenzie ANJ
白细胞介素-25和第2组先天淋巴样细胞（ILC 2）保护宿主免受肠道蠕虫感染，并与不适当的过敏反应有关。先前发现IL-33激活的ILC 2增强保护性组织特异性胰腺癌免疫。在这里，我们发现肠道IL-25激活的ILC 2创造了一个先天的癌症允许微环境。具有较高肿瘤IL-25表达的结直肠癌（CRC）患者的存活率降低，并且表达IL-25 R的肿瘤驻留ILC 2和髓源性抑制细胞（MDSC）增加，这与抗肿瘤应答受损相关。在APC突变驱动的自发性肠道肿瘤发生模型中，IL-25信号传导的消融减少了肿瘤，几乎使预期寿命加倍。在机制上，IL-25促进肿瘤内ILC 2，其维持肿瘤浸润MDSC以抑制抗肿瘤免疫。治疗性抗体介导的IL-25信号传导阻断减少了肿瘤内ILC 2、MDSC和腺瘤/腺癌，同时增加了抗肿瘤适应性T细胞和IFNγ介导的免疫。因此，先天上皮来源的细胞因子IL-25和IL-33以及ILC 2在癌症中的作用不能被概括。CRC中IL-25-ILC 2轴的促肿瘤性质突出了该途径作为针对CRC的新治疗靶点。
Interleukin-25 and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection, and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival, and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired anti-tumor responses. Ablation of IL-25-signalling reduced tumors, virtually doubling life-expectancy in an Apc-mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress anti-tumor immunity. Therapeutic antibody-mediated blockade of IL-25-signalling decreased intratumoral ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor adaptive T cell and IFNγ-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized. The pro-tumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a novel therapeutic target against CRC.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
11.2
作者：
Garg P;Sarma D;Jeppsson S;Patel NR;Gewirtz AT;Merlin D;Sitaraman SV
通讯作者：
Sitaraman SV
影响因子：
--
作者：
Chandrakesan P;Weygant N;May R;Qu D;Chinthalapally HR;Sureban SM;Ali N;Lightfoot SA;Umar S;Houchen CW
通讯作者：
Houchen CW
影响因子：
14.2
作者：
Barlow, Jillian L.;Bellosi, Agustin;McKenzie, Andrew N. J.
通讯作者：
McKenzie, Andrew N. J.
影响因子：
17.1
作者：
Cai H;Scott E;Kholghi A;Andreadi C;Rufini A;Karmokar A;Britton RG;Horner-Glister E;Greaves P;Jawad D;James M;Howells L;Ognibene T;Malfatti M;Goldring C;Kitteringham N;Walsh J;Viskaduraki M;West K;Miller A;Hemingway D;Steward WP;Gescher AJ;Brown K
通讯作者：
Brown K